Dedicated to the Cargo Cults of Biology Science, Biotechnology and the Pharmaceutical Industry.
"So we really ought to look into theories that don't work, and science that isn't science"
Richard Feynman,
Cargo Cult Science,
From a Caltech commencement address given in 1974

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Wednesday, December 21, 2011

If you've made up your mindto test a theory, or you want to explain some idea, you shouldalways decide to publish it whichever way it comes out. If we onlypublish results of a certain kind, we can make the argument lookgood. We must publish both kinds of results. -RF

If we could make one change that could turn the cargo cults into real airports it would be to create a place where the results of all experiments are published. In Cargo Cult Airplane terms, what cargo planes were scheduled to land and did they report on the landing? If you are looking for a big deal struck between big pharma and biotechnology (the departure) you will have no problem finding the publicity. If you are looking for the results of a big pharma/biotech deal you will have to begin conducting research.

Under the terms of the agreement, Pfizer will pay Scripps Research $100 million over a five-year period, during which time scientists from Pfizer and Scripps Research will work together to identify and perform specific projects of mutual interest. Pfizer will pay Scripps Research milestones and royalties on therapeutic compounds created through the collaboration. In addition, Pfizer will have the first right to license many discoveries made at Scripps Research during the agreement.

This particular deal was given journalistic coverage by the San Diego Union Tribune. (Beware the trade PR publications such as Fiercetech and Xconomy)

Pfizer would pay Scripps $20 million a year for five years, he said. Scripps would have full control over how the money is spent.

In return, Scripps would give Pfizer the right to review all of the institute's discoveries, plus the right to license up to 47 percent of them. Pfizer would be able to make such actions only during the five-year funding period.

In order to evaluate the results of this collaboration it is important to know that Pfizer was given access to all of Scripps publicly funded research, not just the work initiated and researched during the five year $100 million deal. It makes the 2011 arrival time even more interesting.

The Pfizer deal replaced Scripps' controversial 10-year alliance with Novartis. The institute came under scrutiny in the early 1990s after the NIH questioned aspects of its initial deal with Sandoz Pharmaceuticals Corp., who later became Novartis. According to the Union Tribune:

During a congressional inquiry, federal officials said the agreement gave Sandoz too much control over Scripps' research priorities, stifled academic freedom and prevented smaller biotechnology companies from competing for access to Scripps' scientific discoveries. The partnership allowed Sandoz to license nearly all of the institute's inventions.

Some legislators suggested that the Scripps-Sandoz deal made the federal government, through its grants to Scripps, a patron of a foreign corporation.

We certainly don't want that to happen. We want pills that make people better when they get sick. After the Scripps-Sandoz partnership, the NIH established policies to clarify how institutions that receive its funds should enter into licensing agreements with for-profit companies.

The institutions' responsibilities include:

Preserving the academic freedom of its scientists.

Ensuring that findings based on taxpayer-funded research are disclosed in a timely manner.

Not entering into agreements that permit a corporate partner to acquire exclusive licensing rights to a discovery without plans to actively develop and commercialize it.

Promoting the manufacturing of its products in the United States.

That is a positive outcome, although not the one intended. A cargo plane landed here, bringing with it a new set of rules. If you are a drug exec or a politician in charge of funding massive organizations like the NIH, this is cargo. This set of rules effects how you do your job. It effects how scientists do their jobs.

What did we get from this deal? What did Pfizer get? One benefit was offered up from the citizens of Palm Beach County Florida. They ponied up $310 million to get Scripps to set up shop in Florida and bring with them high paying jobs. A quick Google search finds a story of hope via the Pfizer deal and an unrelated spin-off from Scripps, Xcovery. On their website Xcovery lists one job. Scripps Florida lists 3 jobs. 4 jobs currently available after $410 million. Are both investments drying up or was there a surge in hiring and thus scientific progress is ? We can't say.

Another potentially related story, "Scripps Research/Pfizer Team Produces a Potential New Painkiller". The team reports on the promising new compound in the April 24, 2009 issue of the journal Chemistry & Biology. The Cravatt group began collaborating with Pfizer in 2003 however to pursue, among other goals, development of fatty acid amide hydrolase (FAAH) inhibitors. This collaboration (began in 2003) led to the discovery of a promising class of inhibitors known as piperidine ureas. This potential painkiller appears to have been sold off as a research tool and can be purchased at various chemical companies. Although not a blockbuster, this is scientific progress. This is a cargo plane that landed with an alternative cargo. It all began in 2003 however.

What really became of this deal? The extensive Pfizer pipeline may contain candidates from this collaboration. Novartis may have picked over the carcass leaving little behind after their ten year manipulation of scientific activity at Scripps. For the Cargo Cult Scientist, this is where research begins. If you want to know what the leaders have been up to you start with a press release. You wait the advertised amount of time and you draw a conclusion on what happened. It really is no different than a laboratory experiment. But who is conducting this research? The NIH and Pfizer executives are the foxes guarding the coup. Quite often a failing project begins to lose favor and piece by piece it begins to disappear. Which brings us back to Feynmans rule of reporting results regardless of outcome. By simply trying to evaluate the outcome of a $100 million dollar deal, we begin to see the complexity of such a human undertaking. Yet we know it is being done everyday by some group of people. They are who we are studying in this research project. What did they do with the money and how are they reporting the value of the investment?

If in fact the drug industry has lost over a trillion dollars in the past decade, this $100 million deal is small potatoes. It tells a story however. Each deal tells a story that is fascinating and worthy of research. There is the psychology of the major players. The structure of scientific research organizations can be studied. Did the Pfizer/Scripps deal solve the productivity issues facing big pharma/biotech R&D?

Imagine an articulate curmudgeon who would dedicate his career to fighting the abuses of scientific authority. Who is the Christopher Hitchens of the scientific community?

While Hitchens was no scientist, he was a brave man who derived his courage from the truth. When you believe you are on the side of the truth, regardless of the accuracy of your assumption, you are empowered to speak up. Hitchens relished a good argument and made a living out of speaking up. I don't believe he engaged in any Cargo Cult intellectualism.

We could use a man like him in our ranks. It would be amusing, as we look to the sky for our Cargo planes, to hear a lone voice, slightly inebriated with a British accent... "They're not coming you God-damned fools!"

"Beware the irrational, however seductive. Shun the 'transcendent' and all who invite you to subordinate or annihilate yourself. Distrust compassion; prefer dignity for yourself and others. Don't be afraid to be thought arrogant or selfish. Picture all experts as if they were mammals. Never be a spectator of unfairness or stupidity. Seek out argument and disputation for their own sake; the grave will supply plenty of time for silence. Suspect your own motives, and all excuses. Do not live for others any more than you would expect others to live for you.” ― Christopher Hitchens

Sunday, December 18, 2011

In January of 2010 Alan Sachs of Merck was interviewed about SIRNA, a subsidiary of Merck who specialized in RNA interference. SIRNA was purchased for 1.1 billion dollars. Before the end was announced they had burned through 1.5 billion dollars. Alan Sachs was their leaders and well aware of the hype:

My background in molecular profiling was around when the Human Genome Project sequence came out in 2000 and 2001, and living through that bubble. What you realize is that the essence of the excitement is correct, and the reduction to practice may make it less-than-anticipated, but it’s still real. The same thing will be true of the RNA therapeutics space. There is a lot of expectation and anticipation. The reality will be somewhere between that and zero. We’d like to think because of the experience we have in our company that we have a clear line of sight on what’s practical within a certain time frame.

This will settle down. The acquisition of Sirna by Merck really set this thing off. We’re three years past that. I think in two more years, you’ll see this settle down, much like in the genomics space. In genomics, many of the opportunities consolidated into a few big players. The same thing will happen here. But the big companies like Merck, Roche, Novartis and Pfizer, that have committed to do this, ultimately will be there. Because of the long-term potential of the modality, not the immediate potential, but the long-term potential. It’s huge.

All of the companies mentioned have ended their RNAi programs, including Alan Sachs' Merck. Alan was correct, It was a huge promise. A huge investment followed and a huge fall from grace has finally been completed. Among the Cargo Cults, Merck had the biggest RNAi airport.

Some investors still believe there is a pot of gold at the end of this rainbow. Here is why the CCS places the science into question.

The talking point among RNAi sympathizers is that monoclonal antibodies had likewise been left for dead back in the 90s. The difference however is that RNAi is a nucleic acid therapy like gene therapy. It is different than protein therapy. The diagrams and animations that depict the mechanism of action (MOA) of RNAi failed to depict the delivery of the small RNA pieces to the gene expressing cell targets. It offered a crisp clean MOA that had the same end result of monoclonal antibody therapy, a reduction in the amount of a specific protein. Without changing the highly simplified approach to biotech research, office bound PhDs ordered their white lab coat staff to run the same ELISAs and western blots to demonstrate knock-down. As a white lab coat staff member, I worked through a microcosm of what was to come back in 2002. My first blog post on RNAi was on May 10, 2006. After four years of thinking about RNAi, working with RNAi, watching others work with RNAi, and most importantly, watching the Cargo Cult leaders deal with the lack of efficacy in RNAi, I had come to the conclusion that this stuff is snake oil. That was several months before Merck bought SIRNA.

Since RNAi didn't work very well in the laboratory, it seemed preposterous that it would work in the clinic. The pharmaceutical industry relies heavily on pharmacy and much less on pharmacology. The two main areas of pharmacology are pharmacodynamics and pharmacokinetics. The former studies the effects of the drugs on biological systems, and the latter the effects of biological systems on the drugs. In broad terms, pharmacodynamics discusses the interactions of chemicals with biological receptors, and pharmacokinetics discusses the absorption, distribution, metabolism, and excretion of chemicals from the biological systems. In contrast, pharmaceutical research is primarily concerned with preparation, dispensing, dosage, and the safe and effective use of medicines. Biotech and Big Pharma leaders put up the money to put RNAi through the latter forms of research. The lack of efficacy left RNAi companies scrambling to explain why RNAi wasn't panning out as a drug. Delivery of the little pieces of RNA to a cell that was actively translating the drug target became a hot topic. In other words, they needed to get a handle on the pharmacology. Delivery of the little pieces of RNA was the reason the leaders decision making had hit a snag.

Currently, delivery of little RNA pieces remains the missing link to the promise. It keeps the promise alive. If the pharmacology techniques were in place we could check on the likes of Alnylam and Tekmira. We should not take their word for the promise of SNALPs, Stable-Nucleic-Acid-Lipid-Particles. We should have a separate organization that works for the FDA and the NIH. This group of scientists would development methods ahead of time to test the claims of for profit organizations who can both profit and cause harm. Other possibilities with RNAi is that they can do no good or they can help what ails us. The important thing for scientists to work on is in the development of a science that will help evaluate claims.

In July of this year Merck ended their RNAi efforts after 5 years and $1.5 billion. They claimed that this was a difficult decision based not on science but on financial needs for the Merck corporation. As usual a learning opportunity was lost. As Feynman said;

In summary, the idea is to give all of the information to help others to judge the value of your contribution; not just the information that leads to judgement in one particular direction or another.

It is our biased opinion here at the CCS that 2011 witnessed a most significant ending to biotechnology's biggest promise of the past decade. I didn't present any data that might have suggested that RNAi works. I left that up to the experts who still claim that RNAi works. As far as putting ones money where ones mouth is, the verdict is in. RNAi is not moving forward in the world of BigPharma.

Here at the CCS we began in 2006 with a strong opinion and we end in 2011 with the same opinion, backed by a huge failure of RNAi in biotechnology and BigPharma. Alan Sachs was right, the promise was huge. That is why the failure is also huge. Huge shifts in thinking are fun places to be in science. Not just in the beginning, like those who jumped on the RNAi bandwagon, but in the end like those who kept the story of N-Rays and cold fusion alive. We have much to learn in the psychology of Cargo Cults. It remains and area in the philosophy of science that is itself a mystery. How do these things happen and why are so many people successful leading failures? What RNAi has taught us is that, in fact, science corrects itself. How do we stray from the truth and how much work goes into correcting ourselves?

Don't believe in the hype of a trendy science story. Believe in the truth. As Alan Sachs would say, there is power in the long term potential of the modality.

Tuesday, December 13, 2011

It appears that the only thing RNA interference has accomplished thus far is a whole lot of disappointment. After my first RNAi experiment worked I was on board. We knocked out IL2 which led to an inhibition of osteoclast formation. Of course that was early on in the research. I later came to the conclusion that the inhibition of osteoclast formation was a fluke. Did I forget to add RANK-L? Would another day of observation have resulted in a full bloom of osteoclasts? As is normal in unreported science, the result was unclear. The probability of what we were hoping for (RNA interference) seemed to diminish with each new attempt at repeating the IL2 knockout.

The company I was working for soon ran out of cash and shut down having never repeated that experiment. Many laboratory workers tried but none could reproduce the results of that simple experiment. The way this type of science works is to have a desired result or even better, a one time observation, and force it to be the truth. The Beer and Pizza diet began. What concentration of RANK-L was used? Where did you buy the cells? Different technicians were brought in to overcome the incompetence of the last. All the while our successful experiment was presented to the investment world in 3 perfectly understandable slides. Just add RNA and away goes osteoclastogenesis.

The reason we went after IL2 was because we were a Bioinformatics company. We alone made the connection of IL2 to the RANK pathway using Bioinformatics. For that brief moment of success, we had added laboratory evidence. It brought out the worst in everyone. We needed this to be true. Our company was hurting and eventually filed for Chapter 7 bankruptcy. If IL 2 had become a drug target for Osteoporosis it would have changed everything.

RNA interference and IL 2 research continue however, with expected outcomes. AVI Biopharma (self proclaimed global leader in RNA based therapeutics) is axing 28% of its staff after missing out on a potentially huge federal contract to make an RNA-based treatment against pandemic flu. RNAi is also used by Dr. Steven Elledge.

Using the power of small interfering RNAs (siRNAs) to silence gene expression, we are now undertaking loss-of-function screens in mammalian cells.

IL 2 is in the news lately with a new retraction from the Bulfone Paus saga.

RNAi and IL2 research could one day lead to important information that will advance the life sciences. What I do is merely research. We find pieces of evidence and we try to figure out what is really going on. The complexity of a pathway is not simply understood by knocking out one of the many proteins involved. Nor is the complexity of RNAi understood by witnessing the many cases of gel manipulation in major publications from Harvard professors. It is odd but not direct evidence that RNAi does not work. IL2 is involved in a few sketchy cases of misconduct as well. It proves nothing.

All we have here is job loss and possible scientific misconduct associated with a couple areas of popular research being conducted by highly successful scientists. Are they Cargo Cult leaders? No comment. Is science correcting itself? Yes.

Friday, December 09, 2011

During the past decade large pharmaceutical companies have pursued an aggressive strategy of mergers and acquisition in an effort to grow their businesses. But an analysis from Burrill & Company suggests the approach has been a failure as these companies have seen the loss of $1 trillion in value during the past decade.

We lost a trillion bucks in a decade? Those of us who enjoy math will stop and reflect on that number. For example, a million seconds lasts about 11 days. A billion seconds lasts about 31.5 years. To be exact, a trillion lasts 31688 years, 269 days, 1 hour, 46 minutes, 40 seconds.

In order to have lost a trillion dollars in ten years we would have to lose $100 billion each year or about $274 million a day.

What does it mean to lose that much money? In that decade I received some of that money in the form of an income. I also spent that money buying reagents and equipment. We paid Retrogen to sequence our DNA and Alphalyse for protein sequencing. While that money was being "lost", others were finding it. Some companies, like Retrogen and Alphalyse, were smart businessmen and women and they positioned themselves to be in line for some of the biopharma largesse.

My car has aged and is now worth less. The value was in fact lost. During the course of the devaluation I enjoyed the usage of my car. It had value and still does, just not as much. Likewise, BioPharma has aged and decreased in value. Unlike my highly reliable Honda Accord however, this baby was a lemon. One of the experts you would trust to make sure you don't pick a lemon is Cargo Cult leader biotech visionary G. Steven Burrill. As the industry was busy losing a trillion dollars G. Steven Burrill was succeeding.

During the course of the trillion dollar loss G. Steven Burrill must have given a warning. Leaders know that losing a trillion dollars is not the goal of any investment. We couldn't actually find any warnings that a trillion dollars was going to be lost. Did G. Steven Burrill succeed in spite of the loss or as a result of the loss? Was the industry loss his gain? How do the Cargo Cults select their leaders when the planes never land?

Thursday, December 01, 2011

One of the things I do from time to time is check the stats on my blog. Most recently I've been getting a lot of hits from people typing Don Polderman into their search engine. There are people who want information. What has Don been up to lately? Has he found a new job, issued some statement regarding his dismissal, published a new paper, invented a new drug, started a biotech company... But a curious thing is happening. If you type Don Polderman into Google, the Cargo Cult Scientist is third on the list!

Are people concerned about the impact of a scientist who published over 500 articles and was fired for scientific misconduct? Are they willing to talk about it? Why hasn't this incident generated a public discussion?

My answer to that question would be cynical. I would cast dispersions on the world of science. I will join the rest of the scientific community who type his name into Google and stumble across this crazy blog. I will skip a detailed research project into the impact of Dons Sins Against Science.

This blog is really about the scientific method. The method can be applied to finding out whether or not your kid is lying to you about brushing their teeth. It can be used to find out if a drug can be manufactured at a 50,000 liter scale or if that drug is useful in treating human disease. The method can be used to find out how much BS Don Polderman has put into the scientific discourse. But professional scientists talk like Don. Judging by the amount of publications, Don was very good at talking. Now we have more information on Don however. Somewhere between the proper application of the scientific method and the kind of scientific misconduct Don Polderman is accused of lies the truth. Was he an outright fraud? Did he really make unintentional mistakes? Is it worth finding out? What about those 500 papers. If they were worth publishing in the first place, is it worth revisiting them? Why, at this point in Dons career, are we abandoning the scientific method? In our opinion now is the most important part of a scientists career to be analyzed using the scientific method. Instead we will brush this one under the rug.

Don Polderman will fade away. But here at the Cargo Cult Scientist, we will hold him in high regard as one of our leaders. Our airports do not bring in cargo. Our airport is a place where people who have no idea how airplanes operate (or even where airplanes come from) become experts in airports and airplanes. The tribesmen are suppose to be obedient and not talk about embarrassing moments experienced by our leaeders, best described in The Emperors New Clothes. We don't know where airplanes come from. But some of us know that our leaders don't either.

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My biotech career is merely a dream. In this dream we are all living on an Island where our ancestors once watched the westerners develop drugs that helped their people fight off disease and suffering. The westerners left and we are now donning their white lab coats and trying to create the drugs ourselves. We have their books, labs, beakers and a handful of drug targets they left behind. But nothing is working.